Dysregulation of the motility of the gastrointestinal tract in diabetic patients is a significant cause of morbidity. The molecular and cellular bases, much less an effective therapeutic management of this disorder, have yet to be identified. The overarching objective of this Program Project is to promote, facilitate and conduct basic, clinical and translational research on the causes of motility disorders with the ultimate goal to identify novel therapeutic treatments. Accordingly, this Program Project is broad, transdisciplinary and interdisciplinary and multidepartmental, but highly focused on the enteric system. The scientific objectives are met through three highly integrated projects that include 8 specific aims, and two cores. The investigators in this application are drawn not only from gastroenterology and physiology but also from neurology, immunology, radiology, surgery and quantitative imaging sciences. Project I (Pathobiology of Diabetic Gastroenteropathy) will study the role of the nNOS and HO/CO pathways in regulating ICC biology. Dysregulation of these pathways results in diabetic gastroenteropathy. Project 2 (Autoimmune and Diabetic Dysmotility) focuses on the role of neuronal autoimmunity as a cause of enteric neuropathy and dysmotility in diabetes. Project 3 (Neurohumoral Regulation in Diabetic Enteropathy) will evaluate a novel integrated neurohumoral axis comprising the incretin, GLP-1, disordered nitrergic neurotransmission and sympathetic dysfunction in diabetic neuropathy in humans. The Administrative Core A will provide leadership and integration of all Program Project activities. The Imaging Core B will provide a centralized resource for storing and sharing image data between projects, will provide advanced software for rigorous quantitative analysis, and will develop new methods for dynamic 3D imaging and image fusion. Through these projects and cores, this highly-interactive program will make significant progress toward understanding the pathobiology of the enteric system in diabetes and translate this knowledge into new diagnostic tools and therapy.